Neurochemical enhancement of conscious error awareness

How the brain monitors ongoing behavior for performance errors is a central question of cognitive neuroscience. Diminished awareness of performance errors limits the extent to which humans engage in corrective behavior and has been linked to loss of insight in a number of psychiatric syndromes (e.g., attention deficit hyperactivity disorder, drug addiction). These conditions share alterations in monoamine signaling that may influence the neural mechanisms underlying error processing, but our understanding of the neurochemical drivers of these processes is limited.Weconducted a randomized, double-blind, placebo-controlled, cross-over design of the influence of methylphenidate, atomoxetine, and citalopram on error awareness in 27 healthy participants. The error awareness task, a go/no-go response inhibition paradigm, was administered to assess the influence of monoaminergic agents on performance errors during fMRI data acquisition. A single dose of methylphenidate, but not atomoxetine or citalopram, significantly improved the ability of healthy volunteers to consciously detect performance errors. Furthermore, this behavioral effect was associated with a strengthening of activation differences in the dorsal anterior cingulate cortex and inferior parietal lobe during the methylphenidate condition for errors made with versus without awareness. Our results have implications for the understanding of the neurochemical underpinnings of performance monitoring and for the pharmacological treatment of a range of disparate clinical conditions that are marked by poor awareness of errors

Norepinephrine directly activates adult hippocampal precursors via beta(3)-adrenergic receptors

Adult hippocampal neurogenesis is a critical form of cellular plasticity that is greatly influenced by neural activity. Among the neurotransmitters that are widely implicated in regulating this process are serotonin and norepinephrine, levels of which are modulated by stress, depression and clinical antidepressants. However, studies to date have failed to address a direct role for either neurotransmitter in regulating hippocampal precursor activity. Here we show that norepinephrine but not serotonin directly activates self-renewing and multipotent neural precursors, including stem cells, from the hippocampus of adult mice. Mechanistically, we provide evidence that beta(3)-adrenergic receptors, which are preferentially expressed on a Hes5-expressing precursor population in the subgranular zone (SGZ), mediate this norepinephrine-dependent activation. Moreover, intrahippocampal injection of a selective beta(3)-adrenergic receptor agonist in vivo increases the number of proliferating cells in the SGZ. Similarly, systemic injection of the beta-adrenergic receptor agonist isoproterenol not only results in enhancement of proliferation in the SGZ but also leads to an increase in the percentage of nestin/glial fibrillary acidic protein double-positive neural precursors in vivo. Finally, using a novel ex vivo "slice-sphere" assay that maintains an intact neurogenic niche, we demonstrate that antidepressants that selectively block the reuptake of norepinephrine, but not serotonin, robustly increase hippocampal precursor activity via beta-adrenergic receptors. These findings suggest that the activation of neurogenic precursors and stem cells via beta(3)-adrenergic receptors could be a potent mechanism to increase neuronal production, providing a putative target for the development of novel antidepressants

The Effects of Methylphenidate on the Neural Signatures of Sustained Attention

BACKGROUND: Although it is well established that methylphenidate (MPH) enhances sustained attention, the neural mechanisms underpinning this improvement remain unclear. We examined how MPH influenced known electro-physiological precursors of lapsing attention over different time scales

Dissociable and common effects of methylphenidate, atomoxetine and citalopram on response inhibition neural networks

Response inhibition is an executive function that allows the detection and modification of unwanted actions. Its underlying neurochemistry and neurobiology have been explored by combining classic neuropsychological paradigms, such as the go/no-go task (GNG), with targeted pharmacology and functional neuroimaging. We sought to further this literature by using single doses of methylphenidate (30. mg), atomoxetine (60. mg), citalopram (30. mg) and placebo to probe dopaminergic, noradrenergic and serotonergic aspects of response inhibition. Twenty-seven (27) healthy, right-handed males participated in a randomised, double blind, placebo-controlled, within subject, crossover fMRI study to examine stop-related BOLD activation correlates of a modified GNG task.Methylphenidate demonstrated activation versus placebo in the pregenual cingulate (dorsal anterior cingulate), right inferior frontal, left middle frontal, left angular and right superior temporal gyri and right caudate. Atomoxetine demonstrated activation versus placebo across a broad network of cortical regions. Both methylphenidate and atomoxetine, but not citalopram, activated superior temporal, right inferior frontal and left middle frontal clusters. Citalopram only activated the left inferior occipital lobe.Taking the above as functionally defined regions of interest, we examined the specificity of stop-related drug activity by comparing mean activations across the four conditions. Only methylphenidate demonstrated drug-specific effects with increased activation of the pregenual cingulate and decreased activation of the caudate.Direct comparison of methylphenidate and atomoxetine showed broad recruitment of prefrontal regions but specific effects of methylphenidate in the pregenual cingulate and caudate revealing dissociable modulations of response inhibition networks

Cortisol and major depressive disorder-translating findings from humans to animal models and back

Major depressive disorder (MDD) is a global problem for which current pharmacotherapies are not completely effective. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has long been associated with MDD; however, the value of assessing cortisol as a biological benchmark of the pathophysiology or treatment of MDD is still debated. In this review, we critically evaluate the relationship between HPA axis dysfunction and cortisol level in relation to MDD subtype, stress, gender and treatment regime, as well as in rodent models. We find that an elevated cortisol response to stress is associated with acute and severe, but not mild or atypical, forms of MDD. Furthermore, the increased incidence of MDD in females is associated with greater cortisol response variability rather than higher baseline levels of cortisol. Despite almost all current MDD treatments influencing cortisol levels, we could find no convincing relationship between cortisol level and therapeutic response in either a clinical or preclinical setting. Thus, we argue that the absolute level of cortisol is unreliable for predicting the efficacy of antidepressant treatment. We propose that future preclinical models should reliably produce exaggerated HPA axis responses to acute or chronic stress a priori, which may, or may not, alter baseline cortisol levels, while also modelling the core symptoms of MDD that can be targeted for reversal. Combining genetic and environmental risk factors in such a model, together with the interrogation of the resultant molecular, cellular, and behavioral changes, promises a new mechanistic understanding of MDD and focused therapeutic strategies

The molecular genetics of executive function: Role of monoamine system genes

Executive control processes, such as sustained attention, response inhibition, and error monitoring, allow humans to guide behavior in appropriate, flexible, and adaptive ways. The consequences of executive dysfunction for humans can be dramatic, as exemplified by the large range of both neurologic and neuropsychiatric disorders in which such deficits negatively affect outcome and quality of life. Much evidence suggests that many clinical disorders marked by executive deficits are highly heritable and that individual differences in quantitative measures of executive function are strongly driven by genetic differences. Accordingly, intense research effort has recently been directed toward mapping the genetic architecture of executive control processes in both clinical (e.g., attention-deficit/hyperactivity disorder) and nonclinical populations. Here we review the extant literature on the molecular genetic correlates of three exemplar but dissociable executive functions: sustained attention, response inhibition, and error processing. Our review focuses on monoaminergic gene variants given the strong body of evidence from cognitive neuroscience and pharmacology implicating dopamine, noradrenaline, and serotonin as neuromodulators of executive function. Associations between DNA variants of the dopamine beta hydroxylase gene and measures of sustained attention accord well with cognitive-neuroanatomical models of sustained attention. Equally, functional variants of the dopamine D2 receptor gene are reliably associated with performance monitoring, error processing, and reinforcement learning. Emerging evidence suggests that variants of the dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) show promise for explaining significant variance in individual differences in both behavioral and neural measures of inhibitory control

Catecholamine modulation of evidence accumulation during perceptual decision formation: a randomized trial

Recent behavioral modeling and pupillometry studies suggest that neuromodulatory arousal systems play a role in regulating decision formation but neurophysiological support for these observations is lacking. We employed a randomized, double-blinded, placebo-controlled, crossover design to probe the impact of pharmacological enhancement of catecholamine levels on perceptual decision-making. Catecholamine levels were manipulated using the clinically relevant drugs methylphenidate and atomoxetine, and their effects were compared with those of citalopram and placebo. Participants performed a classic EEG oddball paradigm that elicits the P3b, a centro-parietal potential that has been shown to trace evidence accumulation, under each of the four drug conditions. We found that methylphenidate and atomoxetine administration shortened RTs to the oddball targets. The neural basis of this behavioral effect was an earlier P3b peak latency, driven specifically by an increase in its buildup rate without any change in its time of onset or peak amplitude. This study provides neurophysiological evidence for the catecholaminergic enhancement of a discrete aspect of human decision-making, that is, evidence accumulation. Our results also support theoretical accounts suggesting that catecholamines may enhance cognition via increases in neural gain

Dopamine D₂ receptor modulation of human response inhibition and error awareness

Response inhibition, comprising action cancellation and action restraint, and error awareness are executive functions of considerable clinical relevance to neuropsychiatric disorders. Nevertheless, our understanding of their underlying catecholamine mechanisms, particularly regarding dopamine, is limited. Here, we used the dopamine D2 agonist cabergoline to study its ability to improve inhibitory control and modulate awareness of performance errors. A randomized, double-blind, placebo-controlled, crossover design with a single dose of cabergoline (1.25 mg) and placebo (dextrose) was employed in 25 healthy participants. They each performed the stop-signal task, a well-validated measure of action cancellation, and the Error Awareness Task, a go/no-go measure of action restraint and error awareness, under each drug condition. Cabergoline was able to selectively reduce stop-signal RT, compared with placebo, indicative of enhanced action cancellation (

Methylphenidate but not atomoxetine or citalopram modulates inhibitory control and response time variability

Background: Response inhibition is a prototypical executive function of considerable clinical relevance to psychiatry. Nevertheless, our understanding of its pharmacological modulation remains incomplete